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Published ahead of print on February 1, 2007, doi:10.1165/rcmb.2006-0409OC

Am. J. Respir. Cell Mol. Biol., Volume 36, Number 6, June 2007, 721-727

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Submitted on November 1, 2006
Revised on January 30, 2007

Repeated Allergen Inhalation Induces Cytoskeletal Remodeling in Smooth Muscle from Rat Bronchioles

Clare G McVicker1, Sum-Yee Leung2, Varsha Kanabar3, Lyn M Moir4, Katharina Mahn3, K. Fan Chung2, and Stuart J Hirst1*

1 Division of Asthma, Allergy and Lung Biology, King's College London School of Medicine, MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Experimental Studies Unit, Imperial College, London, National Heart and Lung Institute, London, United Kingdom, 2 Experimental Studies Unit, Imperial College, London, National Heart and Lung Institute, London, United Kingdom, 3 Division of Asthma, Allergy and Lung Biology, King's College London School of Medicine, MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom, 4 Division of Asthma, Allergy and Lung Biology, King's College London School of Medicine, MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; University of Sydney, Woolcock Institute of Medicial Research, Sydney and Discipline of Pharmacology, Sydney, NSW, Australia

* To whom correspondence should be addressed. E-mail: stuart.hirst{at}kcl.ac.uk.

Airway hyperresponsiveness (AHR) is associated with airway wall structural remodeling and alterations in airway smooth muscle (ASM) function. Previously, in bronchioles from Brown Norway rats challenged by repeated ovalbumin (OA) inhalation, we have reported increased force generation and depletion of smooth muscle contractile proteins. Here, we investigated if cytoskeletal changes in smooth muscle could account for this paradox. Sensitized rats (n=5/group) were repeatedly challenged with OA or saline and the lungs removed 24h after the last challenge. Levels of globular (G) and filamentous (F) actin in bronchioles were determined by DNAse I inhibition and contraction assessed in intact small bronchioles using a myograph. DNAse I inhibition assays showed that G-actin monomers were more abundant (~1F:2G) in extracts from resting small bronchioles from OA- or saline-challenged animals. However, while contractile protein levels in bronchioles were reduced by OA (p<0.05), the proportion of F:G actin was 1.8-fold greater compared with saline challenge (p<0.05). Consistent with induction of F-actin following OA challenge, increases in maximum tension development to carbachol or KCl in small bronchioles from OA-challenged animals were abrogated (p<0.01) by actin cytoskeleton disruption with 0.5 µM latrunculin A. Cytoskeletal stabilization of F-actin with 0.1 µM jasplakinolide potentiated maximum contractions to carbachol or KCl (p<0.05) in bronchioles from OA- but not saline-treated rats. We conclude that alterations in the composition and/or arrangement of the contractile apparatus after OA exposure confer enhanced contractile responses, possibly as a result of increased F-actin content. Such a mechanism may have relevance for AHR found in allergic asthma.




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